Curated by Peter Lansberg,
a Dutch lipidologist and educator, and
reviewed by prof. Philip Barter, Past President of the
International Atherosclerosis Society.

The IAS Statin Newsletter will keep you up-to-date with all recent statin publications, using a curated approach to select relevant articles.

Key publications

Necrotic core volume regresses in Korean patients with LDL-c <70 mg/dl
The benefits of reaching lower LDL-c targets (<70 mg/dl) showed significant benefits in necrotic core volume using virtual histology (VH) IVUS. In this small single center study 61 Korean patients that underwent PCI were evaluated by VH-IVUS. Patients were grouped by achieved LDL-c lower or higher than 70 mg/dl. A re-evaluation took place after a mean follow-up of 8.4 months, an LDL-c <70 mg/dl was observed in 10/61 patients and 14 segments. A higher LDL-c >70mg/dl was present in 51/61 patients in whom 79 segments were evaluated. The strongest predictors of a necrotic core volume (NCV) regression >10% were HDL-c, OR 1.06 (1.00-1.11, p=0.054) and LDL-c <70 mg/dl, OR 3.43 (0.97-12.7, p=0.056. After a multivariate logistic regression analyses an HDL-c increases was associated with an OR 1.07 (1.01-1.15, p=0.210) and LDL-c <70 mg/dl an OR 8.02 (1.58-40.68), p=0.012). According to the authors LDL-c targets of <70mg/dl were uncommon in Korean ASCVD patients; achieving this threshold showed in a relative short period benefits in terms of significant reduction in % NCV.
Seo YH, Seo DJ, Song IG et al.Rationale of decreasing low-density lipoprotein cholesterol below 70 mg/dL in patients with coronary artery disease: A retrospective virtual histology. Intravascular ultrasound study.Cardiology journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29341060Very low LDL-c targets is it worth the costs and effort?
With the introduction of PCSK9ab patients are reaching LDL-c levels that are remarkably lower as what was possible with statins or statins with ezetimibe. In this review Chris Packard discusses the consequences reaching extremely low LDL-c plasma concentrations and provides insights in the debated benefits and potential harms as well. He provides a historic narrative based on his 30 years of experience working in the field of lipids and continues by sharing the data of recent hard clinical endpoint trials to support the current trend of reaching lower targets. The costs of new drugs is increasing exponentially and this puts the physician, managing dyslipidemic patients, in a positon to not only decide what is best and safe to prescribe his patients, but also who should and who should not because of financial constraints. A simple strategy to provide physicians with a step wise approach to select the most appropriate medication for an individual patient is added as well. Treatment targets can be confusing and measuring lipids in a very low range needs to be critically explored. The authors completes this review by addressing these issues and giving a few helpful pointers.
Packard CJ. LDL cholesterol: How low to go?Trends Cardiovasc Med 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29336946

Diabetics and NAFLD what are therapeutic options – meta analysis
Despite the impressive CVD mortality reduction observed in developed economies over the recent decades, a source of serious concern is the global increase in the incidence and prevalence of diabetes mellitus type 2 (DM2) – metabolic syndrome(MS). Associated with DM are liver anomalies where obesity and insulin resistance play an important, and the latter even causal role. The prevalence of hepatic steatosis in patients with T2DM was projected to be 30–50%. In this meta-analysis the authors reviewed current literature on the safety and efficacy of therapeutic strategies directed at non-alcoholic fatty liver disease (NAFLD) in diabetic patients (DM2). From the initial 397 selected abstracts they collected 23 relevant articles. The following treatment strategies were evaluated: thiazolidinedione’s (TZD), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and statins. The studies included were randomized controlled, observational, and open-label designs, as well as three meta-analyses. The standard approach of metformin + lifestyle (diet and weight loss) showed modest improvements in steatosis but no effects on fibrosis. In patients treated with TZD’s, fibrosis and NASH but more than half of the studied patients showed no response. GLP-1 RAs were successful in reducing transaminases as well as steatosis and due to their primary effect improved insulin sensitivity and reduced body weight to some extent. However, no effects on the resolution of NASH or fibrosis was noted. Statin improved transaminases as well and showed a mixed result on NASH and fibrosis. The authors concluded that all evaluated treatments were safe to use in DM2 patients with NAFLD. Long term histological improvements were not that impressive. They considered TZD’s a viable option to treat NASH and improve fibrosis but noted the lack of long term outcomes.
Mills EP, Brown KPD, Smith JD et al.Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a review of efficacy and safety.Therapeutic advances in endocrinology and metabolism 2018; 9:15-28. http://www.ncbi.nlm.nih.gov/pubmed/?term=29344336

Inflammation and oxidative stress in high and moderate ASCVD risk patients, improves with atorvastatin 20 as well as 40 mg
The role of inflammation in atherosclerosis and CVD risk is now firmly established and has increased in prominence after the results of the CANTOS trial, evaluating the benefits of IL1β-ab on CVD risk reduction independent of lipid lowering. In this study the authors established the benefits of atorvastatin 20 and 40 mg on Plasma markers of oxidation and inflammation: ET-1, CRP, MPO, total nitrite, lipid peroxides (TBARS), and superoxide dismutase (SOD) activities and lipids were measured at baseline and after 12 weeks treatment. Participants were 210 Jordanian patients that presented to a university hospital cardiology clinic. Patients were stratified into low, moderate and high ASCVD risk. In the low ASCVD risk patients (0-1 major ASCVD risk factor) all inflammatory and oxidative markers were significantly lower and SOD significantly higher compared to the higher risk patients. Both dosages of 20 and 40 mg atorvastatin reduced LDL-c as well as CRP, MPO, nitrite, and TBARS while SOD activity increased. These changes were independent from the lipid lowering effects of atorvastatin. The authors concluded that irrespective of the low (20 mg) or high (40 mg) dosage of atorvastatin there were significant improvements in the key inflammatory and ant-oxidative plasma markers that potentially contribute to the ASCVD risk reductions observed with atorvastatin.
Mayyas F, Baydoun D, Ibdah R, Ibrahim K. Atorvastatin Reduces Plasma Inflammatory and Oxidant Biomarkers in Patients With Risk of Atherosclerotic Cardiovascular Disease.Journal of cardiovascular pharmacology and therapeutics 2018:1074248417753677. http://www.ncbi.nlm.nih.gov/pubmed/?term=29343081

Adherence is a formidable challenge but carries with it great rewards
The two major challenges in reducing CVD risk are initiating the right treatment and continuing this treatment indefinitely, but for most lifelong. To highlight the challenges of statin adherence a systematic review of primary prevention patients is presented in this article. They performed a systematic review of the literature up to December 2016, that evaluated hard clinical endpoints such as cardiovascular fatal or nonfatal events and all-cause mortality. They included 17 articles, of which 4 were case–control, nested in a retrospective cohort design and the other 11 were cohort studies. Best adherrers were compared to worst adherrers in 7 studies. In 3 studies (317 603 participants) evaluated IHD and observed an 18% (14%-22%; I2=0%) relative risk reduction for CVD outcome. A pooled analysis of 2 studies (131 477 participants) presented a 47% (36%-56%; I2=84,7%) lower risk in adherent participants. 2 studies (155 726 participants) showed a pooled reduction in CVD risk of 26% (18%-34%; I2=0%); and for mortality a 49%(39%-57%; I2=62.4%) lower risk. The remaining 4 studies (147 859 participants) compared the most adherent group with the rest. The adherent patients ended up with a 22% (6%-27%, I2=0) lower CVD risk. The authors emphasize the importance of statin adherence in a primary prevention setting. They also recommended stricter definitions to standardize measures of treatment adherence, enabling better comparisons between studies.
Martin-Ruiz E, Olry-de-Labry-Lima A, Ocana-Riola R, Epstein D. Systematic Review of the Effect of Adherence to Statin Treatment on Critical Cardiovascular Events and Mortality in Primary Prevention.Journal of cardiovascular pharmacology and therapeutics 2018:1074248417745357. http://www.ncbi.nlm.nih.gov/pubmed/?term=29343082

High dose atorvastatin reduced CIN in ACS – PCI patients
Patients requiring coronary angiography for diagnostic or therapeutic purposes (PCI) are at significant risk for developing contrast induced nephropathy (CIN). Evidence has been accumulating that peri-procedural high dose atorvastatin can reduce this risk. In this randomized controlled trial 496 Chinese ACS patients were assigned to atorvastatin 10 mg (N=247) one day before and 3 days after contrast administration or atorvastatin 40 mg (n=249), daily during the same peri-procedural period. CIN was evaluated by measuring serum creatinine (SCr) and Cystatin C (CyC). CIN, based on SCr developed in 31 patients using 10 mg and in 16 patients using 40 mg; 12.6% vs 6.4% (P=0.02). Using CyC as marker for CIN, the numbers were 90 patients vs 46 patients respectively, 36.4% vs 18.5% (P<0.001). A multivariate analysis confirmed the protective effect of high dose atorvastatin on developing CIN. The authors suggested that CyC performed better as a marker for CIN and that the non-lipid lowering effects of atorvastatin e.g. reducing oxidative stress and anti-inflammatory properties were to a large extent responsible for the observed reduced incidence of CIN in Chinese ACS patients.
Fu N, Liang M, Yang S. High Loading Dose of Atorvastatin for the Prevention of Serum Creatinine and Cystatin C-Based Contrast-Induced Nephropathy Following Percutaneous Coronary Intervention.Angiology 2018:3319717750903. http://www.ncbi.nlm.nih.gov/pubmed/?term=29343076

Statins and fusidic acid a drug combination we need to avoid?
Rhabdomyolysis (RM) remains the most important serious side effect that patients using statins can experience. A critical factor to develop this life-threatening complication, is the plasma concentration of statins; when increased so is the risk for RM. A number of concomitant drugs are known to affect the breakdown or removal of statins from plasma. Fusidic acid (FA), up until now was, not on that list. The authors, after being confronted with a sever RM case who used atorvastatin and FA, reviewed the available literature on reported RM when FA and statins were combined. In all they discovered 29 case reports. Mean ages of affected patients was 66 years and the interval between starting the combination and RM occurrence was 21 days; 28% of these patients did not survive. Exploring the WHO VigiBase, 182 cases surfaced. Mean age 68 years duration of co-administration was 31 days and fatal RM was noted in 24% of the patients. Based on these observations the authors concluded that there is substantial risk of developing RM after a relatively long duration of combined statin and FH treatment. Particularly disturbing was the high fatality rate. If there is no alternative for FA, the authors suggest interrupting the use of statins for the duration of the FA treatment and re start statin one week after FA is stopped.
Deljehier T, Pariente A, Miremont-Salame G et al.Rhabdomyolysis after co-administration of a statin and fusidic acid: an analysis of the literature and of the WHO database of adverse drug reactions.Br J Clin Pharmacol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29337401

Yu X, Zhang J, Gu Y et al.CHILD Syndrome Mimicking Verrucous Nevus in a Chinese Patient Responded Well to The Topical Therapy of Compound of Simvastatin and Cholesterol.Journal of the European Academy of Dermatology and Venereology : JEADV 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29341259